The immune system excludes cancer by immunosurveillance in the early stage of cancer development and by anti-tumor immunity after cancer manifestation. On the other hand, the cancer in a cancer microenvironment acquires an immune escape mechanism by affecting an immune checkpoint mechanism such as PD-1 (programmed cell death-1)/PD-L1 (programmed cell death-1 ligand-1) or PD-L2 route, or CTLA-4 (cytotoxic T-lymphocyte associated antigen 4)/CD80 or CD86 route and directly suppressing activated T cells, or by indirectly suppressing the activated T cells through induction of regulatory T cells or bone marrow-derived regulatory cells and production of an immunosuppressive humoral factor (IL-10, TGF-β, indoleamine 2,3-dioxygenase (IDO), or the like). The cancer immunotherapeutic agent using an immunomodulator that suppresses these immune escape mechanisms has been vigorously under clinical development for use as a promising therapeutic agent alone or in combination with other immunomodulators or existing anticancer agents.
It is known that PD-1 is expressed in T cells or the like and is responsible for the immune checkpoint (Pharmacogenomics and Personalized Medicine, 2014; 7: 357-365, Current Opinion in Immunology, 2014; 27: 89-97). When PD-L1 and PD-L2, which are ligands of PD-1, are bound, activation of T cells is suppressed, and thereby immune response is hindered. For example, activated effector T cells recognize cancer cells and produce inflammatory cytokines such as interferon gamma. On the other hand, cancer cells react to the inflammatory cytokine and increase the expression of PD-L1, and thus suppress the immune response by PD-1-positive effector T cells. Thus, cancer cells have a function of escaping from the immunosurveillance against cancer by utilizing the PD-1/PD-L1 route. Therefore, the PD-1/PD-L1 route is considered to be one of the main molecular mechanisms of immunosuppression in the cancer microenvironment (Pharmacogenomics and Personalized Medicine, 2014; 7: 357-365, Current Opinion in Immunology, 2014; 27: 89-97).
As an antibody that inhibits the binding of PD-1 and PD-L1, nivolumab, which is an anti-PD-1 antibody, has been marketed as a therapeutic agent for malignant melanoma and non-small cell lung cancer, and pembrolizumab has been marketed as a therapeutic agent for malignant melanoma. Other several anti-PD-1 antibodies or anti-PD-L1 antibodies also have been under clinical development as a therapeutic agent for malignant melanoma, non-small cell lung cancer, renal cell carcinoma, recurrent glioblastoma, head and neck cancer, stomach cancer, esophageal cancer, colorectal cancer, bladder cancer, urothelial carcinoma, hepatocellular carcinoma, prostate cancer, Merkel cell carcinoma, non-Hodgkin's lymphoma, Hodgkin lymphoma, B cell lymphoma, acute myeloid leukemia, or chronic hepatitis C. In double blind randomized phase 3 study Check Mate-066 in which nivolumab was used as a first-line drug against malignant melanoma, it was reported that overall survival in 72.9% of a nivolumab group was extended; however, the existence of patients who failed to respond was also recognized.
Regarding the immunotherapy, clinical trial result of combination therapy in which drugs having different mechanisms are combined, for example, clinical trial result of combination therapy of nivolumab, which is the anti-PD-1 antibody against malignant melanoma, and ipilimumab, which is an anti CTLA-4 antibody, has been reported (Pharmacogenomics and Personalized Medicine, 2014; 7: 357-365, Current Opinion in Immunology, 2014; 27: 89-97).
As the antibody that inhibits the binding of CTLA-4 and CD80 or CD86, ipilimumab, which is the anti CTLA-4 antibody, has been marketed as a therapeutic agent for malignant melanoma, and has been under clinical development as the therapeutic agent for non-small cell lung cancer, small cell lung cancer, prostate cancer, and the like.
Regarding an IDO inhibitor, INCB-024360 has been under clinical development as a therapeutic agent for malignant melanoma, fallopian tube cancer, ovarian cancer, peritoneal carcinoma up to now.
Dendritic cells present in blood and lymphatic tissues are known to activate T cells via inflammatory cytokines. It is reported that AXL, MER and TYRO3, which are subfamilies of receptor tyrosine kinases in dendritic cells, bond to type I IFN receptor (IFNAR) and induce suppressor of cytokine signaling 1 and 3 (SOCS 1/3) to inhibit Toll-like receptor 4 (TLR4) signal, and suppress the expression of inflammatory cytokines, and thereby the immune response is controlled to be negatively regulated. In addition, it is reported that the immune function is deteriorated by AXL (Cell. 2007 Dec. 14; 131(6): 1124-36.).
The AXL is a protein having a cellular transmembrane domain in the center, a tyrosine kinase domain on the carboxyl terminal side, and an extracellular domain on the amino terminal side. So far, overexpression of AXL has been reported in acute leukemia, astrocytoma, breast cancer, colon cancer, esophageal cancer, gastrointestinal stromal tumor, stomach cancer, hepatocellular carcinoma, Kaposi's sarcoma, lung cancer, melanoma, ovarian cancer, osteosarcoma, pancreatic duct adenocarcinoma, renal cell carcinoma, prostate cancer, thyroid cancer, and endometrial carcinoma (Mol. Cancer Ther. 2011 October; 10(10): 1763-73.).
The MER is a protein having a cellular transmembrane domain in the center, a tyrosine kinase domain on the carboxyl terminal side, and an extracellular domain on the amino terminal side. Overexpression of MER has been reported in acute leukemia, acute lymphocytic leukemia, glioma, osteosarcoma, prostate cancer, schwannoma, mantle cell lymphoma, and rhabdomyosarcoma cells (Nat Rev Cancer. 2014 December; 14(12): 769-85.).
In addition, it is reported that MER lowers immune function (J Clin Invest. 2013 Aug. 1; 123(8): 3231-42.). It is reported that MER inhibits the production of inflammatory cytokines such as IL-12 in dendritic cells and suppresses the activation of CD4 positive (for positive, it may be expressed as “+”, and the negative may be expressed as “−”) T cells and CD8+ T cells. It is reported that expression of IL-12, which is inflammatory cytokines, is induced by tumor transplantation in MER knockout mice compared to wild type mice, and tumor growth and metastasis are suppressed.
It is known that 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide (hereinafter, referred to as “compound A” in some cases) or a pharmaceutically acceptable salt thereof has an inhibitory effect on various kinases including AXL, and inhibits the proliferation of tumor cells in which these kinases are involved, and thus is useful as an active ingredient of a pharmaceutical composition for treating cancer (Patent Documents 1 and 2).